Childhood obesity is a major public health problem in the United States where nearly 17% of children are obese and another 15% are overweight. Emerging evidence suggests that early life exposure to chemical obesogens may increase the risk of obesity by affecting hormonal systems involved in adipogenesis, weight homeostasis, or metabolism. Perfluoroalkyl substances (PFAS) are a class of man-made chemicals used in stain/water repellant textiles, nonstick coatings, and food packaging. Growing evidence from animal, human, and experimental studies shows that these chemicals may be obesogens and affect cardio-metabolic endpoints as well. Despite this, there are few prospective human studies characterizing the obesogenic effects of PFAS, and even fewer investigating the molecular mechanisms of PFAS action. We will use the HOME Study, a prospective birth cohort of 375 women and their children from Cincinnati, OH to address these gaps and determine if PFAS exposures during three distinct periods of development are associated with body composition, cardio-metabolic risk markers, and relevant biological intermediates. Women in our study have serum PFOA concentrations two-times higher than US pregnant women due to their proximity to a fluoropolymer manufacturing plant, thus allowing us to examine the impact of high exposure to this chemical. We have measured serum concentrations of four PFAS (PFOA, PFOS, PFNA, and PFHxS) in pregnant women during the 2nd trimester and their children at 3 years of age. Concentrations will also be measured at 12 years of age. We will determine if higher exposures to these PFAS at these times in development are associated with: 1) Growth from birth to 12 years of age and state-of-the-art measures of body composition at 12 years of age; 2) Cardiometabolic risk factors, including central adiposity, blood pressure, and fasting lipid, glucose, and insulin levels at 12 years of age; 3) Cortisol concentrations in infant meconium and adiponectin or leptin levels in serum collected from neonates and 12 year olds; and 4), Changes in leukocyte DNA methylation at >485,000 loci in child blood samples collected at delivery and 12 years. These aims scale from the child to molecular level, allowing us to test the hypothesis that prenatal PFAS exposures adversely affect clinical endpoints in children across the first 12 years of life and related molecular pathways. By identifying potentially modifiable obesity risk factors using these data, we will provide critical data to scientists and policy makers about the health effects of PFAS exposures at three distinct life stages. These data may serve as a model for other potential chemical obesogens that have similar structures or act via comparable mechanisms.